HIF1a N-terminus hyperacetylation and anticancer mechanism of hydroxamic-HDACi

描述(由申请人提供)：HIF1a N-末端超乙酰化和羟基HDACi组蛋白脱乙酰酶抑制剂(HDACi)的抗癌机制显示出令人鼓舞的抗肿瘤活性。然而，其抗肿瘤作用的机制尚不清楚，这阻碍了基于HDACi的治疗方法的临床设计的优化和癌症患者治疗结果的改善。本研究的目的是通过抑制缺氧诱导因子1α(HIF1a)--一种负责血管生成和肿瘤发展的蛋白质--来研究基于羟胺的HDACi的抗癌机制。中心假设是：HDAC同工酶-HIF1a轴的抑制介导了羟胺-HDACi的抗肿瘤作用，因为特定的HDAC同工酶阻止了HIF1a的超乙酰化；当这些HDAC同工酶被抑制时，HIF1a在其N端被高乙酰化，这破坏了其转录活性和蛋白质的稳定性。因此，识别和靶向这些特定的HDAC同工酶是抑制HIF1a、血管生成和肿瘤生长的一种新方法。提出了三个目标。目的1：我们将鉴定HIF1a N-末端能被羟胺-HDACi高乙酰化的特定赖氨酸残基，并验证HIF1a N-末端超乙酰化破坏HIF1a功能和稳定性的假说。目的：我们将确定实现HIF1a N末端超乙酰化所必须抑制的HDAC同工酶，并验证HIF1a N末端乙酰化水平受多个HDAC同工酶调节的假设。目的：通过验证阻断HDAC同工酶-HIF1a轴可以抑制HIF1a，并损害血管生成和肿瘤生长的假说，我们将在体外和体内确定抑制特定HDAC同工酶的生物学后果。我们的建议将阐明一种新的机制，通过它可以通过特定的HDAC同工酶调节HIF1a，并将为为什么一些HDACi可以抑制HIF1a，而其他HDACi不能。这一知识支持了不同类型的HDACi在癌症和其他疾病中的治疗活动，在这些疾病中，HIF1a在病因和病理上都有牵连，对于选择正确的HDACi类型进行治疗至关重要。

DESCRIPTION (provided by applicant): HIF1a N-terminus hyperacetylation and the anticancer mechanism of hydroxamic HDACi Histone deacetylase inhibitors (HDACi) have shown encouraging antitumor activities. However, the mechanism mediating the antitumor effect is still unclear, which prevents the optimization of clinical designs of HDACi- based therapies and the improvement of treatment outcomes for patients with cancer. The goal of this proposal is to investigate the anticancer mechanism of hydroxamic-based HDACi involving the inhibition of hypoxia inducible factor 1 alpha (HIF1a), a protein responsible for angiogenesis and cancer development. The central hypothesis is: the inhibition of HDAC isozyme-HIF1a axis mediates the antitumor effect of hydroxamic -HDACi because specific HDAC isozymes prevent HIF1a hyperacetylation; and when these HDAC isozymes are inhibited, HIF1a is hyperacetylated at its N-terminus, which disrupts its transcriptional activity and protein stability. Therefore, identifying and targeting these specific HDAC isozymes represents a novel approach for suppressing HIF1a, angiogenesis, and tumor growth. Three aims are proposed. Aim 1: We will identify the specific lysine residues that can be hyperacetylated by hydroxamic-HDACi at the HIF1a N-terminus and test the hypothesis that HIF1a N-terminal hyperacetylation disrupts HIF1a function and stability. Aim 2: We will identify the HDAC isozymes that must be inhibited in order to achieve HIF1a N-terminal hyperacetylation and test the hypothesis that the HIF1a N-terminal acetylation level is regulated by multiple HDAC isozymes. Aim 3: We will determine the biological consequences of inhibiting specific HDAC isozymes in vitro and in vivo by testing the hypothesis that disruption of HDAC isozymes - HIF1a axis can inhibit HIF1a, and impair angiogenesis and tumor growth. Our proposal will elucidate a novel mechanism by which HIF1a can be regulated by specific HDAC isozymes and will provide a mechanistic rationale for why some HDACi can inhibit HIF1a, but others cannot. This knowledge underpins the therapeutic activities of different types of HDACi in cancer and other diseases where HIF1a is etiologically and pathologically implicated and is vital for selecting the right type of HDACi for therapy.